There has long been evidence that RA and related chronic arthritides involve both genetic and infectious etiopathogenetic factors. Recently, increased attention has focusing on the role of infectious agents suspected of involvement. In the past, an immense effort has been made to detect such agents in these disorders using chiefly culture and immunologic methods, without notable success. These approaches suffer from the need for prior knowledge about the growth requirements or immunology of the organisms being sought and therefore have been narrow in scope. Thus, the many negative results obtained cannot easily be interpreted. To justify another such effort it is necessary to overcome these limitations. The present approach is believed largely to achieve this. It employs the polymerase chain reaction with primers capable of amplifying essentially all known bacteria, which, as detected by this method, includes the Chlamydiae, Rickettsiae and mycoplasmas, along with essentially all other prokaryotes of medical interest. This method, as we had originally proposed it, was since applied by two groups, to the successful identification the causative agents in two previously idiopathic diseases, Whippel's disease and bacillary granulomatosis, thus clearly validating our original rationale. To apply this approach to RA, we had first to resolve the problem of contamination, the chief limitation to achieving the theoretical sensitivity of the PcR. By succeeding with this we are now able to achieve sensitivity of 1 organism per reaction in practice in clinical specimens. Thus this method can now provide significant information about both the presence and absence of bacterial DNA in synovial specimens. Recent studies have explored extending the generic bacterial PCR to an in situ method that will allow a clear distinction between potential pathogens and contaminants and will also provide insight into the histologic context of any detected amplimers. The combination of these approaches should provide a powerful means of obtaining unambiguous information about the presence or absence of biologically relevant bacteria in RA synovial specimens. In this way the hypothesis that persistent synovial infection is necessary for maintenance of active rheumatoid synovitis will be tested, as will more complex hypotheses addressing bacterial involvement in RA. Analogous. studies of the HLA B27-related disorders and their association with bacterial infection are also proposed.